The angiopoietin-like protein 4 (ANGPTL4/FIAF) has been identified as a multifunctional signal protein. It is produced by a variety of tissues, and secreted into the blood stream in glycosylated, oligomerized, native and cleaved isoforms, to modulate physiological events such as angiogenesis, cell differentiation and the crosstalk between liver, brain, adipose and muscle tissue in lipid and glucose metabolism. In addition, the expression and isoform appearance of ANGPTL4 are modified by the intestinal microbiota. With eye on an effective strategy to improve health by ANGPTL4, we focus in this review on (i) health issues associated with ANGPTL4 expression, including obesity, type II diabetes, cardiovascular diseases and cancer, (ii) several modulators of FIAF of chemical, microbiological, food and host origin, and (iii) the correlation of the specific ANGPTL4 isoforms with these modulators and health effects.